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| 采用新型微泡技术靶向AC005229.4/Cul1抑制肝癌对索拉非尼耐药的研究 |
| Inhibition of liver cancer resistance to sorafenib by targeting AC005229.4/Cul1 with novel microbubble technology |
| 投稿时间：2024-09-03 修订日期：2025-02-21 |
| DOI： |
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| 中文关键词: 液态氟碳纳米粒 索拉非尼 耐药 晚期肝癌 LncRNA |
| 英文关键词:liquid fluorocarbon nanoparticles Sorafenib Drug resistance Advanced liver cancer LncRNA |
| 基金项目:国家自然科学基金项目（面上项目，重点项目，重大项目） |
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| 中文摘要: |
| [目的]探究索拉非尼治疗晚期肝癌的耐药机制, 寻觅新分子靶点为提升索拉非尼疗效提供新策略。
[方法]通过数据库及生信分析，锁定Cul1为索拉非尼耐药关键因子，其所在泛素化连接酶SKP1-Cul1-F-box（SCF）复合物可促肝癌细胞增殖。AC005229.4是Cul1基因启动子区反义链转录出来的lncRNA，能促进Cul1表达，筛选出miR-520b-3p可直接靶向Cul1及抑制AC005229.4间接下调Cul1。构建多功能液态氟碳纳米粒（PFH/ICG/miR-520b-3p/PLGA-PEI）携miR-520b-3p靶向AC005229.4/Cul1以抑制Cul1表达、增加索拉非尼药敏性。
[结果]成功构建了多模态成像功能的液态氟碳纳米粒，体内外实验显示，纳米粒释放的miR-520b-3p有效抑制Cul1表达，提升索拉非尼耐药肝癌细胞药敏性。
[结论]采用新型微泡技术靶向AC005229.4/Cul1，可抑制Cul1表达、提升肝癌的索拉非尼耐药细胞的药敏性，为晚期肝癌靶向研究与治疗提供重要理论基础和有效的技术手段。 |
| 英文摘要: |
| [Objective] To investigate the mechanisms of resistance to sorafenib in the treatment of advanced liver cancer and identify novel molecular targets, thereby providing new strategies to enhance the efficacy of sorafenib.
[Methods] Utilizing database searches and bioinformatics analyses, Cul1 was identified as a key factor in sorafenib resistance, with its ubiquitin ligase complex, SKP1-Cul1-F-box (SCF), promoting proliferation in liver cancer cells. AC005229.4, an lncRNA transcribed from the antisense strand of the Cul1 gene promoter region, enhances Cul1 expression. miR-520b-3p was screened for its ability to directly target Cul1 and indirectly downregulate Cul1 by inhibiting AC005229.4. A multifunctional liquid perfluorocarbon nanoparticle (PFH/ICG/miR-520b-3p/PLGA-PEI) was constructed to carry miR-520b-3p targeting AC005229.4/Cul1, thereby inhibiting Cul1 expression and increasing sensitivity to sorafenib.
[Results] A liquid perfluorocarbon nanoparticle with multimodal imaging capabilities was successfully constructed. Both in vitro and in vivo experiments demonstrated that the miR-520b-3p released from the nanoparticle effectively inhibited Cul1 expression and enhanced the sensitivity of sorafenib-resistant liver cancer cells to the drug.
[Conclusion] Utilizing novel microbubble technology to target AC005229.4/Cul1 can inhibit Cul1 expression and enhance the sensitivity of sorafenib-resistant liver cancer cells, providing an important theoretical foundation and effective technical means for targeted research and treatment of advanced liver cancer. |
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